Alzheimer's disease ("AD") is a disorder of unknown etiology. A pervasive and deleterious effect of AD is a decreasing deficit in cognitive function. Several approaches to the treatment of this disorder are currently being investigated. To date, however, only one therapeutic approach has evidenced sufficient clinical safety and efficacy to warrant approval for commercialization by the United States Food and Drug Administration ("FDA"). This therapeutic approach focuses on inhibition of acetylcholinesterase ("AChE"). AChE is an enzyme that degrades the neurotransmitter acetylcholine ("ACh"). By inhibiting this degradation process, the ACh neurotransmitter remains in the neural cleft for increased time periods, thereby increasing the chemical and functional effects of the neurotransmitter, e.g., improvement in cognitive function. Two such AChE inhibitors approved by the FDA are 1,2,3,4-tetrahydro-9-acridinamine (tacrine, THA; "COGNEX") and donepezil (E2020; "ARICEPT"). An AChE inhibitor approved for commercialization in Europe is rivastigmine (ENA713; "EXELON"). A significant side effect associated with all three of these compounds is nausea and/or vomiting. This side effect can limit the maximum dose that a physician may otherwise desire to provide to a patient, for obvious reasons, e.g., the side effect may cause patients to not take all of the required doses, or the side effect may cause patients to stop taking the medication entirely.
While inhibition of AChE is one approach to resolving clinical deficits associated with AD, another approach would be to increase production of ACh. It has been reported that antagonists to the serotonin receptor 5-HT3, increase the neuronal release of ACh. See for example Ramirez, M. J., et al., 712:2 Brain Res. 274 (1996); Crespi, D., et al. 35:4 Pharmacol. Res. 351 (1997); and Roychoudhurg, M. and Kulkani, S. K., 19:1 Methods Find Exp. Clin. Pharmacol. 43 (1997). It has also been reported that the density of 5-HT3 receptor recognition sites are not altered in patients with AD as compared to age-matched controls. Barnes, N. M., et al., 1:3-4 Neuroreport. 253 (1990). Antagonists to the 5-HT3 receptor are also reported to inhibit emesis (i.e., vomiting). See, e.g., Parikh, P. M. et al. 33:1 Indian J. Cancer 17 (1996).
Quinoline derivatives having AChE activity have been disclosed. U.S. Pat. Nos. 5,190,951; 5,540,934; and 5,300,517.
Compounds having multiple therapeutic mechanisms are desirable. For example, a compound that can both inhibit AChE activity and increase the neuronal production of ACh would be preferred for the treatment of neurological disorders such as AD, where the beneficial link between ACh, inhibition of AChE, and AD have been clinically established. This invention is directed to this, as well as other, important ends.